The investigation of novel and innovative treatment approaches for long-term management of HIV-infection has intensified due to the growing number of infected individuals worldwide and the constraints of resistance, toxicity and convenience associated with lifelong therapy. Current treatment relies entirely on antiretroviral drugs targeting various stages of the life cycle of HIV, rather than on leveraging the immune system. However, the boosting of HIV-specific immune responses in chronic infection offers a vast potential for synergy with antiretroviral drugs, thereby contributing to durable control of viral replication. The Project Leader's laboratory developed a novel immunotherapeutic agent that delivers plasmid DNA to dendritic cells after topical skin application. This therapeutic vaccine has demonstrated immunological and clinical benefit in chronically infected rhesus macaques in combination with antiretroviral therapy. The Program Project proposes the improvement of the safety features of the vaccine and the transition of the product to HIV-1 infected human subjects. This includes pre-clinical toxicity studies using the product manufactured for clinical use. Upon approval of the IND by the FDA we propose to initiate a pilot study to determine the safety, tolerability and immunogenicity of one or two immunizations in patients with viral load suppressed by HAART. Immunogenicity of the vaccine product will be intensively studied using assays developed in this Program Project and through collaborations. The study is aimed to determine whether a one immunization schedule could replace and improve the two consecutive immunization schedule originally administered in the monkey studies, in order to simplify and improve the clinical management of DermaVir. The funding of this project will greatly contribute to the Clinical Development Plan which focuses on bringing DermaVir to the market to benefit the majority of HIV infected patients. Specific Aim 1. Pre-clinical testing programs a. Safety, biodistribution and genetic toxicity of DermaVir in mice b. Topical and general toxicity of DermaVir in swine Specific Aim 2. Pilot clinical testing trial Safety and immunogenicity of DermaVir in chronically-infected patients treated with HAART.